Depression is a major cause of mortality and morbidity worldwide. Its etiology is unknown. Current therapeutic treatments are effective in only half of patients and, when effective, work slowly. There is increasing evidence that a weakening of excitatory synaptic transmission between cells in multiple cortico-mesolimbic reward circuits is induced in rodents by chronic stress, perhaps underlying the wide range of behaviors affected by stress. Innovation: We discovered in the previous grant cycle that selective serotonin reuptake inhibitors act slowly to restore this weakened synaptic excitation. Based on the rapid antidepressant actions of ketamine, we identified a novel class of compounds that we predict will act rapidly to strengthen pathologically weakened excitatory synapses and can thus be predicted to exert a fast acting antidepressant action with fewer side effects than ketamine. Specifically, we will test the hypotheses that Partial inverse agonists of the benzodiazepine binding site of GABAA receptors containing a5 subunits (PIAGRA) will produce a rapid and persistent restoration of a range of behaviors that are affected by chronic stress paradigms in rats and mice and that they will restore the strength of pathologically weakened excitatory synapses, as measured in electrophysiological and biochemical assays. Approach: Our preliminary data show that a unique PIAGRA compound (L-655,078) restores normal sucrose preference and social interaction within 24hrs in rats subjected to two chronic stress paradigms and restores the strength of AMPAR-mediated synaptic excitation and GluA1 expression in hippocampal synapses in rats subjected to chronic stress. We also observed that synapses formed by hippocampal projections to neurons in the nucleus accumbens display activity-dependent long-term potentiation. We propose to test the following specific aims. 1: Determine the persistence and generality of PIAGRA's antidepressant actions on a range of appetitive and innate behaviors (food, social interactions, sex). 2: Determine the mechanism of action of PIAGRA at the level of synaptic circuits. 3: Determine the effects of stress and PIAGRA on hippocampal-NAc excitatory synapses. We will use multiple chronic stress paradigms to produce changes in reward behavior, then test whether PIAGRA compounds produce rapid (<24 hrs) and persistent normalization of these behaviors and determine how long these beneficial actions persist. We will then use electrophysiological recording to test the strength of excitatory interactions, along with several biochemical and molecular correlates, in brain tissue taken from these animals 24 hrs after injection of the compounds. Outcome: Our study will provide a thorough proof-of-concept test of a novel class of AD compounds at several levels of analysis from behavior to molecules, as encouraged by the NIMH's Research Domain Criteria initiative. Evidence of a beneficial therapeutic action in rodents after chronic stress, and the identification of key circuits at which they act, will encourage a test of their therapeutic effect in depressed patients.